Congestive heart failure (CHF), a major cause of death in the US, is a growing problem in our aging population. This proposed project is directed at developing radionuclide molecular imaging technologies using a clinical pinhole SPECT/CT scanner to quantify the changes in deformation, perfusion, innervation, and metabolism in the heart using the spontaneous hypertensive rat (SHR) as a model of hypertensive related pathophysiology. The similarity in the response to CHF treatment for humans and for SHR suggests that the SHR is an appropriate model for a major class of heart failures that are due to hypertension. The combined application of both microPET and pinhole SPECT provides tools to improve and evaluate developed technology. In addition, ex vivo magnetic resonance diffusion tensor imaging, simultaneous PET/MRI, and histopathology will provide mechanical and biochemical structural correlates. Preliminary data using the SHR model indicate that such technological developments are possible. The new technologies will improve diagnosis, monitor progression, and evaluate therapy for the disease. Because our technological approach uses pinhole clinical SPECT/CT and radiopharmaceuticals that reflect flow, metabolism, innervation, and structural mechanics, the developed techniques can be directly translated to clinical instruments for better management of patients with heart failure. The uniqueness of this project is the development of techniques for estimating input function from projections of a slow rotating camera imaging fast circulation in a rat, the application of mechanical models to detect early changes in deformation in the hypertrophied heart, and the quantification of the kinetics of tracers using models of the image detection process in which the effects of attenuation, scatter, and collimator response are determined from Monte Carlo simulations. Combining new dynamic and conventional clinical imaging protocols with improved descriptions of the heart (physiological, mechanical, and biochemical) will allow us to obtain better specification of the heart's properties and to study how molecular changes in the heart caused by disease affect these properties. Innovations for pinhole-based tomography of animals that are useful to the scientific community are collimator design, gantry motion calibration, reconstruction algorithms for cone beam geometry, and spatiotemporal modeling of attenuation and scatter. The development of these technologies will provide methods for quantifying perfusion, biochemical kinetics, and wall dynamics.